It is accepted dogma that typically ovulation of a single, fertilizable ovum each menstrual cycle completes a course of oogenesis that began during fetal development. It is not known, however, why from among the thousands of follicles present from birth, only a relative few are recruited each cycle to grow while at the same time others remain at rest. It is also not known why from the host of follicles maturing in each ovary, typically only a single follicle escapes atresia and is selected to ovulate each cycle. Since the vast majority of follicles fall victim to atresia (greater than 99%), understanding the selection of the follicle destined to ovulate is frought with the inherent difficulty of studying the rare exception rather than the predominant rule. One must be extremely careful to distinguish follicle growth that culminates in ovulation (gametogenic follicle growth) from that ending in atresia.
The latter stages of oogenesis in adults (i.e. folliculogenesis) are known to depend, to a large degree, on a complex interplay of hormones from the hypothalamus, pituitary and ovary. However, even though much more is understood about these endocrine relationships today, what determines the fate of an individual follicle remains largely unknown. Since in higher primates both ovaries are functional, the maturation of a single follicle with the potential to ovulate brings with it the obvious concomitant of one active and one quiescent (gametogenically) ovary each cycle. It is not known how just, typically, a single follicle matures to ovulation on only one ovary each cycle, even though both ovaries are perfused by a common systemic circulation.
Three glycoprotein hormones, luteinizing hormone (or LH), follicle stimulating hormone (or FSH) and human chorionic gonadotropin (or hCG) can act on the ovary to stimulate steroid synthesis and secretion. LH and FSH are secreted by the pituitary and together play a central role in regulating the ovarian menstrual cycle and ovulation. hCG is secreted by the developing placenta from the early stages of pregnancy and its role is to maintain steroid secretion by the corpus luteum, which is necessary to preserve the conceptus during early pregnancy.
In the normal or natural cycle, there is a midcycle surge in LH concentration in blood which is followed by ovulation. An elevated estrogen level, which is brought about by the endogenous secretion of LH and FSH acting to stimulate ovarian follicular maturation, is required for the LH surge to occur. The estrogen mediates a positive feedback mechanism which results in the increased LH secretion.
It is now known how to employ exogenous hormonal stimulation by administering mixed human menopausal gonadotropins, i.e. a combination of FSH and LH, as a prelude to ovulation or follicle aspiration for oocyte collection in in vitro fertilization techniques. Women and monkeys treated with such human menopausal gonadotropins often fail to demonstrate a timely LH surge despite serum estradiol levels ordinarily sufficient to elicit positive feedback for the LH surge. It has been concluded that the human menopausal gonadotropins stimulate the production of an ovarian factor or factors which blocks the pituitary LH response to estrogen as presented by Hodgen, Fert. Steril 38:281-380 and Schenkan and Hodgen J Clin Endocr Metab 57:50-55, 1983 and gonadotropin releasing hormone (GnRH). This blockage of GnRH action on the pituitary may be the mechanism by which the human menopausal gonadotropin stimulation prevents the estrogen mediated positive feedback of LH secretion. Non-human primates have been employed in research because of their extensive mimicry of many anatomic, functional and temporal characteristics of the hypothalamic-pituitary-ovarian-uterine axis in women. The individual variation in serum estrogen levels of endocrine normal individuals in response to human menopausal gonadotropin stimulation, as seen in these primates, is well recognized clinically also. This has resulted in the adoption of an individualized regimen for ovulation induction by human menopausal gonadotropin/hCG. Although LH surges do occur spontaneously, their appearance is sufficiently infrequent that hCG is routinely administered to induce ovulation.
Administration of human menopausal gonadotropins to ovulatory monkeys produces familiar bilateral ovarian hyperstimulation with attendant superphysiologic elevations of circulating estradiol. Despite these elevated estrogen levels, the monkeys usually failed to manifest timely gonadotropin responses to estrogen positive feedback, i.e., stereotypically these normal, intact, cycling primates do not have the expected midcycle like LH surges despite escalating levels of serum estradiol that usually exceed 400 pg/ml during 12 days of human menopausal gonadotropin therapy. An absence of spontaneous LH surges has also been observed when human menopausal gonadotropin induced ovarian hyperstimulation occurs in post-partum monkeys. These observations fit with the frequent clinical finding that when endocrinologically normal patients are given human menopausal gonadotropins to increase the number of follicles/ova available for in vitro fertilization and embryo transfer therapy, hCG is usually required for the final maturation of these follicles.
It is well established that the appropriate application of mixed exogenous gonadotropins has proved efficacious for ovulation induction or for multiple egg retrieval during in vitro fertilization therapy in women. Such in vitro fertilization therapy generally comprises the steps of inducing fertilization by administering exogeneous human menopausal gonadotropins, harvesting the ovulated follicles, combining the ovum with spermatozoa in vitro and transferring the conceptus into the uterus. However, ovarian stimulation through exogeneous gonadotropins for in vitro fertilization therapy is notoriously difficult to manage and the lack of uniform success with conventional human menopausal gonadotropin medications, those containing FSH and LH in nearly equal amounts, is widely appreciated. Individual responses to human menopausal gonadotropins vary markedly, thereby complicating patient management even when the most flexible (individualized) protocols are used as presented by Kenigsberg, Littman and Hodgen, Fert. & Steril. in press 1984.